Results from a new study at Hutchinson Cancer Research Cancer in Seattle suggests that chimeric antigen receptor (CAR) T-cell therapy can be further improved for multiple myeloma. The approach relies on a class of drugs known as gamma-secretase inhibitors (GSIs), several of which have been studied to treat Alzheimer disease but were never approved for that use.
CAR T-cell therapies, such as tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta), are engineered to produce to a receptor that hones in on a specific protein on the surface of cancer cells. For multiple myeloma, the CAR T-cell therapy nearing FDA approval is engineered to target a protein called BCMA.
In the new study, published in Blood, researchers showed that treating myeloma cells with a GSI increased the amount of BCMA they produced on their surface. When tumors were treated with both a GSI and BCMA-targeted CAR T-cells, the cancer was more sensitive to the treatment. By comparison, the tumors that only received CAR T-cell therapy cells initially responded but the cancer eventually came back.
According to the study authors, there seems to be evidence that myeloma cells can avoid being attacked by CAR T-cells by sloughing off BCMA; however, antigen loss as a cause of treatment resistance seems to be a bigger problem with CD19 CAR T-cell therapies.
Another potential hurdle for CAR T-cells is that bits of the freed target antigen can remain in the circulation, acting as a decoy and drawing away CAR T-cells that might otherwise attack tumor cells, according to the study. Researchers said they are unsure how this may affect BCMA CAR T-cell therapy.
The Fred Hutchinson research team worked to find ways to increase the amount of BCMA on myeloma cells. This led them to the enzyme gamma secretase, which cells rely on to rid themselves of BCMA from their surface. Gamma secretase is also involved in the production of the amyloid proteins that are thought to drive the development of Alzheimer disease.
In a series of experiments, researchers showed the treating myeloma cells with a GSI, in cell lines and those taken from the bone marrow of patients, dramatically increased the amount of BCMA the cells expressed. This increased the BCMA level and improved CAR T-cell binding to myeloma cells.
They also found evidence in laboratory studies that GSIs could impair T-cell activity, but it occurred only when the drugs were given at very high doses, according to the study authors.
In an analysis of 3 patients with multiple myeloma who participated in a phase 1 clinical trial, patients received 3 doses of a GSI over 5 days. The treatment nearly tripled the percentage of myeloma cells with measurable expression of BCMA and increased expression in myeloma cells by a median of 33-fold.
Researchers note that they will continue to monitor GSI on T cells.